Final Diagnosis -- intravascular large B cell lymphoma (A progressive multifocal neurological syndrome in a 42 year old woman)

DIAGNOSIS

The final diagnosis was that of intravascular large B cell lymphoma.

DISCUSSION

We present a case of intravascular lymphoma (IVL) in a young woman where the diagnosis remained elusive until post mortem.

Intravascular lymphoma / intravascular lymphomatosis, also termed angiotropic lymphoma, was first described in 1959 by Pfleger and Tappeiner (8) but it has only recently been included in the WHO classification of lymphoma as a distinct subtype of diffuse large B cell lymphoma (8). IVL is a malignancy of adults with a median age at presentation of 67years (age range 13-85years), which affects females and males equally (9), although the cutaneous variant seems to affect females more than males (2).

IVL can involve virtually any organ such that the clinical presentation is hugely variable and non-specific, making the diagnosis difficult. The most common symptoms at presentation, in 55% cases (8), are systemic symptoms (B symptoms) including one or all of fever, weight loss, night sweats. Cutaneous lesions and neurological lesions are seen in 40% and 35% respectively (8) but the range of cutaneous lesions and neurological symptoms is very wide (8). IVL is said to mimic other neurological conditions (3) by presenting with sensory/ motor deficits, neuropathy, speech disturbance, seizures, myoclonus, vertigo (8), encephalopathy (1,3), dementia (1) among others. Other presenting symptoms include pain and fatigue as well as symptoms depending on organ involvement which can evolve to multi-organ failure. (8). The non-specific presentation symptoms are often accompanied by a significant deterioration in performance status as we saw in our case.

Diagnosis is difficult due to the non-specificity of symptoms such that a clinician requires a high index of suspicion of IVL in the first instance. Furthermore diagnosis is difficult as there is no single diagnostic test. Hematological abnormalities including anemia, raised LDH and beta microglobulin levels are described in 63%, 86% and 82% of cases IVL respectively, and a raised ESR is seen in 43% cases. A monoclonal serum component is seen in 14% cases. There are no pathognomonic radiological findings. In IVL involving the CNS ischemic foci are the most common observation, and the main differential diagnosis is vasculitis (8). However, Ponzoni et al state that CNS involvement is diagnosed by neuroimaging in only half of cases. CSF analysis may show raised protein, usually less than 200mg/dl, and if a lymphocytosis is present it is mild, usually less than 10 cells/ mm3. (5). CSF cytology is usually negative (5) although has been reported as positive in a case with very advanced disease (tumour mass with periventricular extension) as well as a case with extensive involvement of spinal leptomeningeal vessels (5). Bone marrow is involved in approximately 1/3 of cases (8) and decision to perform bone marrow biopsy may be the result of unexplained anemia or fever. As there is cutaneous involvement in over 40% cases (8) random skin biopsy may reveal IVL. In a series of 8 patients with neurological involvement by IVL reported by Beristain et al (1), 3 underwent brain biopsy and only 1 was diagnostic for IVL. The authors stress the importance of including leptomeninges in the biopsy.

In IVL enlarged atypical lymphoid cells with scant cytoplasm are seen in the lumina of small and intermediate sized blood vessels with or without the presence of thrombi. (9) The tumour cells show morphological features intermediate between centroblasts and immunoblasts in that they have variable numbers of nucleoli (8). Mitoses can be frequent (8, 9). If the tumour involves the liver, spleen or bone marrow, malignant cells are seen in the sinusoids. Minimal extravascular location of neoplastic cells can be seen (9) but in many instances endothelial infiltration is actually of mature non-neoplastic T cells (1). The cause of neurological dysfunction is infarction secondary to vascular occlusion by fibrin thrombus or by tumour volume. More than 90% cases have a B cell immunophenotype showing positive staining with CD20 and CD79a, and rarely CD79a alone (8). Whilst there have been case reports of a T cell variant, current WHO guidelines state that this should be regarded as a separate entity. Positive staining with CD5 is reported in 38% cases (9) and some cases have displayed a germinal centre immunophenotype (MUM-1 negative, CD10 positive) (8). In addition to the histological features above a so called "Asian variant" has been described in which the lymphocytes are admixed with other non-neoplastic cells including histiocytes with prominent hemophagocytosis (8). These patients are more likely to have multiorgan failure, hepatosplenomegaly and pancytopenia (9). Beristain's review of 8 cases of IVL with neurological involvement revealed the presence of infarcts in 7/7 cases where neuropathological examination was available, and additionally hemorrhage was seen in 2/7 cases (1).

IVL is an aggressive lymphoma (9) with a poor response to chemotherapy (9). A better prognosis is seen with the cutaneous variant (9). With the exception of limited cutaneous disease, patients with IVL should be regarded as having disseminated disease and should therefore be considered for polychemotherapy (8). A review of 38 cases showed stage IV disease in 68% cases (2) and according to Ponzoni et al all autopsied cases show disseminated disease, although our case illustrates that this is not always the case. Patients treated with anthracycline-based chemotherapy have a 3 year overall survival in the region of 30% (8). Long term follow up data in case series is limited. Remission is most commonly observed in patients with skin-limited disease, low disease burden and good performance status (8). Good performance score, cutaneous variant, stage one disease, and use of chemotherapy were all independently associated with improved survival in the review of 38 cases (2). Transient clinical improvement on steroid therapy has been reported in the literature (4) and it can be dramatic (1) and perhaps steroid treatment played some role in prolonging survival in our case. Furthermore disseminated disease was not evident in our case, which may also have impacted on survival. Recent potential therapeutic approaches include anti CD20-containing regimens (7)

It is remarkable that these malignant lymphocytes do not extravasate through the blood vessel walls. Normal interaction between neoplastic cells and endothelium comprises 2 phases, "docking" and "locking", the former involving adhesion molecules including I-CAMs and the latter involving integrins (6). In a series of 6 cases of IVL, there was a consistent lack of CD29 (beta1 integrin) and CD54 (ICAM-1) expression by immunohistochemistry, implicating these adhesion molecules in the intravascular confinement (6). It is not understood why there is a predilection for the CNS (1) in so many of these cases.

In summary we present the case of a young woman with progressive multifocal neurological dysfunction in whom a diagnosis antemortem was not possible despite a long clinical course. We highlight the variability in presentation of IVL, the route to diagnosis, the histological features and the poor outcome.